Potential Roles and Key Mechanisms of Hawthorn Extract against Various Liver Diseases

The genus Crataegus (hawthorn), a flowering shrub or tree, is a member of the Rosaceae family and consists of approximately 280 species that have been primarily cultivated in East Asia, North America, and Europe. Consumption of hawthorn preparations has been chiefly associated with pharmacological benefits for cardiovascular diseases, including congestive heart failure and angina pectoris. Treatment with hawthorn extracts can be related to improvements in the complex pathogenesis of various hepatic and cardiovascular disorders. In this regard, the present review described that the presence of hawthorn extracts ameliorated hepatic injury, lipid accumulation, inflammation, fibrosis, and cancer in an abundance of experimental models. Hawthorn extracts might have these promising activities, largely by enhancing the hepatic antioxidant system. In addition, several mechanisms, including AMP-activated protein kinase (AMPK) signaling and apoptosis, are responsible for the role of hawthorn extracts in repairing the dysfunction of injured hepatocytes. Specifically, hawthorn possesses a wide range of biological actions relevant to the treatment of toxic hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease, and hepatocellular carcinoma. Accordingly, hawthorn extracts can be developed as a major source of therapeutic agents for liver diseases.


Introduction
Liver disease is associated with high prevalence, increased mortality, and a substantial health care burden. By 2017, approximately 1.5 billion people were suffering from chronic liver disease (CLD), which, along with liver cirrhosis, accounts for 2 million annual deaths worldwide [1,2]. Non-alcoholic fatty liver disease (NAFLD) accounts for a major component (60%) of CLD, other components of which include hepatitis B and C viruses (38%) and alcohol consumption (2%) [1]. Acute liver failure is mainly a consequence of viral infection and drug-induced liver injury in the developing and developed worlds, respectively [3]. Although vaccination and novel antiviral agents have lowered the incidence of virus-induced liver diseases, including cirrhosis, considerable risk factors, including metabolic syndrome, obesity, and alcohol and drug misuse/overuse, still lead to various liver disorders [4,5]. However, there are no approved drugs currently available for managing various liver diseases, including NAFLD, non-alcoholic steatohepatitis (NASH), alcoholic liver disease (ALD), liver cirrhosis, and hepatocellular carcinoma (HCC).
A wide spectrum of risk factors affecting the liver, including obesity, drugs, alcohol, environmental pollutants, irradiation, and toxicants, can induce excessive oxidative stress in liver tissues and perturb the hepatic defense system against oxidative damage [6]. In this and insufficient sources of active compounds. Thus, further investigations need to be performed for data of chemical profiling, reference compounds, and reliable validation for quality assurance of hawthorn.

Hepatoprotective Effect
The liver is an important solid organ that filters blood input from the gastrointestinal tract, decomposing toxicants and disposing of harmful materials from the body [24]. Lack of proper hepatic function due to oversupply of food, alcohol, medications, toxicants, and other harmful factors can lead to some degree of liver damage, suggesting abnormalities in the synthesis, processing, and secretory functions of hepatocytes. Hepatic injury is characterized by abnormal liver function due to increased activity of serum biochemical markers, and histological findings of damaged hepatocellular structures [25]. Reactive oxygen species (ROS) may be a key determinant in the development and aggravation of liver dysfunction because oxidative stress can primarily oxidize hepatocellular structure components, including DNA, proteins, and lipids [26]. In addition, pathological apoptosis excessively eliminates hepatocytes through the release of harmful cytokines and maximal immune responses [27].
Hawthorn extracts prevented liver damage induced by a high-fat/cholesterol/triglyceride/ fructose diets, alcohol treatment, LPS, CCl 4 , cadmium, and partial hepatectomy in rodents and HepG2 cells, via inhibition of oxidative injury and apoptosis. Serum transaminase (AST and ALT) levels are frequently increased in liver injury because they leak into peripheral blood in cases of abnormal hepatocellular integrity [27]. Hence, regulating both serum markers within normal limits can represent liver protection and maintenance of liver function. The extracts of C. oxyacantha [28], C. aronia [29], C. monogyna [30], and C. pinnatifida [31][32][33][34][35] significantly decreased serum AST and ALT levels, which were markedly elevated by high-fat, high-cholesterol, high-triglyceride, and high-fructose feeding. In addition, these hawthorn species lowered the serum levels of ALP, GGT, total bilirubin, and direct bilirubin in the above animals [28,30,32,34,35]. Histological analysis of liver tissues using high fat/cholesterol/fructose diet-induced rodents revealed that hepatocytes highly express pyknotic nuclei, vacuolation, sinusoidal distension, necrosis, damaged endoplasmic reticuli, swollen and pleomorphic mitochondria, distorted intercellular spaces, irregular nuclear membranes, nuclear chromatin condensation, and cellular degeneration, suggesting that these diets contribute to liver damage. Hawthorn extracts improved these hepatic tissue injuries through antioxidant mechanisms, including the regulation of Nrf2 and ARE expression [30,36,37]. Remarkably, polyphenols obtained from hawthorn peels and flesh exerted a potent hepatoprotective action by efficiently ameliorating biochemical markers, hepatic lipid peroxidation, and liver tissue injury via the regulation of apoptosis-related proteins and antioxidant enzymes dysregulated by a high-fructose diets [38].
C. pinnatifida and C. oxyacantha are involved in the protection of liver injury after alcohol exposure [10,31,[39][40][41][42]. In HepG2 cells and Sprague Dawley rats, alcohol toxicity caused increased DNA damage in liver cells, and abnormal alcohol-metabolizing enzyme activity, biochemical marker levels, and histological findings. After co-treatment of these rats with an ethanol extract of C. pinnatifida, ALDH activity increased in the hepatic tissues [40], with decreased levels of serum AST, ALT, and GGT [31,42], and improved cell necrosis and sinusoidal distension [31]. In addition, the extract prevented alcoholic damage to HepG2 cells through the antioxidant defense system [10] and suppressed the catalytic activity of CYP2E1 [41], despite alcohol being a strong inducer of oxidative stress and CYP enzymes. Although the C. oxyacantha extract exhibited similarities against alcohol inducers, the hepatoprotective effects of the extract can be distinguished by the increase in liver glycogen levels, lack of which easily causes hepatic steatosis and insulin resistance [42]. In contrast to other causative factors, including lipopolysaccharides (LPSs), CCl 4 , cadmium, and hepatectomy, which are harmful to the liver, hawthorn extracts also reversed abnor-mal serum markers and impaired liver tissue via the inhibition of PARP cleavage and TUNEL-positive hepatocytes, and activation of the hepatic antioxidant system [43][44][45][46][47].

Antisteatotic Effect
Hepatocytes frequently become steatotic from several triggers, such as alcohol and metabolic or toxic stress. Steatosis is considered the most common and earliest stage of liver injury and is characterized by the accumulation of extra lipid droplets in the liver [48]. The presence of significant fatty infiltration in hepatic tissue is predominantly implicated in dysregulated lipid homeostasis, which is attributed to an imbalance between de novo lipogenesis and fatty acid oxidation [49]. Oxidative stress also possibly plays a pivotal role as an influential trigger for the initiation of hepatic steatosis and progression to inflammation or fibrosis [50]. Specifically, in NAFLD, the most common liver disease representing hepatic steatosis, oxidative stress, and impaired lipid metabolism may be two crucial mechanisms underlying the development of NAFLD in the progeny of obese mice [51]. Regarding these key triggers for the onset of hepatic steatosis, various transcriptional factors and hepatic enzymes have been implicated to regulate hepatic steatosis [52].
Oxidative stress and hepatic cholesterol metabolism dysfunction often cause fatty livers. Hawthorn reduces fat deposition in liver tissue by altering multiple intrahepatic factors associated with ROS generation, antioxidant defenses, lipogenesis, fatty acid oxidation, fatty acid uptake, and bile acid efflux. This review suggests that haw pectin obtained from Crataegus pinnatifida fruits may be effective in decreasing hepatic fat storage. Further animal and human studies investigating the additional efficacy and various genes that encode markers leading to hepatic steatosis are required. In addition, further studies regarding the role of C. pinnatifida on the interactions between the gut and liver in the management of hepatic steatosis are needed as the extract decreases hepatic total cholesterol levels by impeding cholesterol absorption from the gut through the suppression of fibroblast growth factor receptor 4 (FGFR4) mRNA and protein. Figure 2. Inducer, rodent, hawthorn species, experimental results, and underlying mechanism of preclinical studies on hawthorn extract exhibiting antisteatotic activities related to liver pathogenesis. ApoE, apolipoprotein E; AMPK, AMP-activated protein kinase; LDL, low-density lipoprotein; MCD, methionine choline deficient; TC, total cholesterol; and TG, triglyceride. Table 2. Antisteatotic effects and molecular mechanisms of hawthorn extract.

Models Doses Results and Mechanisms Reference
Ethanol extract of C. cuneata (fruits) In vivo, male mice fed with high-fat diet 130 mg/kg ↓Hepatic steatosis induced by high-fat diet ↓Hepatic TC Hepatic cholesterol metabolism ↓Hepatic HMG-CoA reductase mRNA ↓Hepatic HMG-CoA reductase promoter activity ↓Hepatic NFκB p65 mRNA [68] Water extract of C. aronia (herba) In vivo, male Wistar rats fed with high-fat diet 200 mg/kg ↓Hepatic steatosis induced by high-fat diet ↓Liver weight ↓Fat deposition in liver tissue [29] 70% ethanol extract of C.

Anti-Inflammatory and Antifibrotic Effects
Hepatic injury and steatosis are commonly accompanied by inflammation and fibrosis. While hepatic inflammatory and fibrotic activation are essential for tissue repair and wound healing in response to injury, dysregulation and overexpression of inflammatory and fibrotic mediators in liver tissue can play a crucial role in accelerating liver damage [78]. Hepatic inflammation can be induced by oxidative stress, apoptosis, and inflammationrelated signaling activation [79,80]. Initiation of inflammation is closely associated with macrophage infiltration and neutrophil recruitment to the liver, which elicit the secretion of various inflammatory cytokines. Overproduction of pro-inflammatory cytokines and chemokines in the liver generates and enhances hepatic fibrosis, mediated by active hepatic stellate cells (HSCs) and multiple extracellular matrix (ECM) deposition [81]. Hence, alteration in liver inflammation is regarded as an undoubtedly important target for improving liver disorders and preventing fibrogenic reactions.

Anticancer Effects
To fight against malignant cancer and discover novel anticancer drugs, the pharmacological effects of suppressing the viability and proliferation of fast-growing cancerous cells are of utmost importance. Specifically, chemotherapy efficiently eliminates uncontrolled cancer cells by activating apoptotic pathways, cell cycle arrest, and inducing autophagic clearance. Indeed, various chemotherapeutic agents targeting these mechanisms are predominantly used because tumor cell survival often relies on aberrant function of the regulators of apoptosis, autophagy, and cell cycle progression [83,84]. In addition, elucidating the structure-activity relationship (SAR) of efficient candidates with anticancer activities might help determine their functional groups and assess their therapeutic potency to inhibit proliferation and mediate cell death pathways [85].
The antiproliferative property of hawthorn against liver cancer cells has been largely determined using a cell-based MTT assay in HepG2 and Hep3B cells. Among the various species of hawthorn, C. pinnatifida, C. monogyna, and C. armena have significantly suppressed the cell viability of human hepatoma cells, including HepG2 and Hep3B cells [20,[86][87][88][89][90], while the water extract of C. aronia effectively increased the level of reduced intracellular antioxidant glutathione and glutathione disulfide in HepG2 cells, indicating no significant cytotoxicity against tumors. Interestingly, the 80% ethanol extract of C. monogyna exhibited dose-dependent cytotoxic activity toward HepG2 cells, although the extract had abundant polyphenolic compounds and zinc, possessing antioxidant properties [87]. In addition, the cytotoxic activity of C. monogyna extract was specific to HepG2 and showed no harmful effects in non-tumor normal human skin fibroblast BJ cells at the same concentration [87]. The selective cytotoxicity of HepG2 and protective effects on BJ cells of C. monogyna can be explained by the high amounts of bioactive antioxidant compounds and zinc present in its extract [87]. However, due to the abundant content of phenolic acid in 80% methanol extracts of C. monogyna, the extract might have displayed weaker cytotoxicity toward HepG2 cells, with IC 50 values ranging from 88.45-318.72 µM, compared with those of the anticancer drug ellipticine (IC 50 , 1.21 µM) treatment [91].
Meanwhile, it should not be assumed that the potential anticancer activity of different hawthorn species is less effective than that of conventional chemotherapeutic drugs because of the high predominance of the antioxidant compounds found in their extracts. The stronger cytotoxicity of hydroxy-olean-12-en-28-oic acid triterpenoids obtained from the berries of C. pinnatifida (IC 50 < 5 µM) was confirmed by comparing its IC 50 with that of the positive control cisplatin (IC 50 > 5 µM) using the MTT assay implemented in HepG2 cells [88]. In addition, lignans, a group of phenolic constituents found in the extract of the seeds of C. pinnatifida showed stronger growth inhibitory activities (IC 50 , 30.96-39.97 µM) than 5-fluorouracil (IC 50 = 40.34 µM) against HepG2 cells [92,93]. Hence, the selective toxicity toward hepatoma cells and the potent effectiveness of hawthorn extract might be a therapeutic advantage compared to conventional anticancer drugs.
The cytotoxic properties of phenylpropanoids from C. pinnatifida fruits in HepG2 and Hep3B cells via proapoptotic signaling, autophagy induction, and cell cycle arrest are considered noteworthy [89,94]. Similarly, the ethanol extract of C. pinnatifida fruits exerted inhibitory activities against the viability of HepG2 cells, and the effects were supported by apoptosis induction by regulating caspase-3 activity and genetic expression of Bax and Bcl-2 [86]. Phenylpropanoids may have been partly responsible for the anticancer effects of the C. pinnatifida extract against HepG2 cells. Interestingly, some phytochemical results suggest a possible SAR that might help understand the pharmacological activities of phenylpropanoids in attacking hepatic cancer cells [94]. For example, the distinctive cytotoxicity of crataegusanoids A and B, which belong to phenylpropanoids, can be increased by the presence of the phenyl group at C-7" and (E)-2-styryl, respectively, against two hepatoma cell lines. In addition, SAR analysis of crataegusoids C and D showed that two methoxy-substituted groups at the C-3 position were associated with potent cytotoxic activities of both compounds against HepG2 cells [94].
In summary, C. pinnatifida, C. monogyna, and C. armena exhibited significant anticancer effects on human hepatoma cells, whose activity was comparable to that of conventional chemotherapy to treat HCC. In addition, because of the abundant amounts of antioxidant constituents found in the extract and chemical compound groups of these plants, hawthorn treatment could result in selective cytotoxicity in HepG2 cells. The antioxidant property of hawthorn suggests its relative safety, even when prescribed for a long time or coadministered with anticancer drugs. The antitumor activity of hawthorn, triterpenoids, phenylpropanoids, and lignans isolated from C. pinnatifida might be potent candidates contributing to the cytotoxicity of hawthorn. Among the four pentacyclic triterpenoids, the IC 50 of corosolic acid was the lowest in HepG2 cells (Figure 4, Table 4). Thus, further indepth investigations of the molecular mechanisms, pharmacology against drug resistance, and SAR related to anticancer activities of various materials, including corosolic acid, are required.

Safety of Hawthorn
It is necessary to evaluate and confirm the safety of hawthorn for its use as a therapeutic agent for various liver diseases. When the water extract of C. pinnatifida fruits (126 g/kg crude drugs) was administered to Kunming mice, none of the subjects died, and when the water extracts of C. cuneata and C. scabrifolia were administered to Kunming mice, only one subject died. The 50% lethal dose (LD 50 ) of crude drugs exceeded 126 g/kg; therefore, the toxicity of hawthorn fruit is expected to be very low [95]. The LD 50 of the water extract of C. oxyacantha leaves was measured as 13.5 g/kg, with no dead subjects and no behavioral changes from up to 10 g/kg [96]. The 70% ethanol extract of C. aronia leaves did not cause any behavioral changes, and there were no dead subjects up to 5000 mg/kg [97]. In addition, when the water extract of a whole plant of C. aronia (up to 2000 mg/kg, for 28 days) was administered orally to Wistar rats, there were no signs of acute toxicity or fatality [98]. Therefore, the LD 50 of C. aronia leaves and the whole plant may possibly exceed 5000 mg/kg and 2000 mg/kg, respectively. Although the LD 50 values vary depending on the hawthorn species, medicinal parts, and extraction methods, all the LD 50 values in rodent models exceeded 2000 mg/kg, which is considered relatively safe compared to aspirin (LD 50 , 200 mg/kg) and metformin (LD 50 , 1000 mg/kg).
A systematic review demonstrated that the adverse events of C. extract WS ® 1442 (160-1800 mg/day for 3-24 weeks) include dizziness, gastrointestinal disturbance, headache, and palpitations [99], but another study emphasized that no significant adverse events and no specific drug interactions were observed after administration of WS ® 1442 [100].
As demonstrated above, hawthorn extracts displayed significant hepatoprotective activities against various stimulants, including fat diet, alcohol, heavy metals, and hepatectomy. Thus, considering animal studies and reviews of clinical trials on the safety of hawthorn, the plant can be regarded as a drug that can be prescribed with little toxicity in patients with liver diseases, despite further studies.

Discussion
Recently, herbal interventions have emerged as a therapeutic option for managing pathophysiological changes in various liver diseases, including NAFLD, viral hepatitis, and HCC [11,101]. Hawthorn is efficacious and has high potential to be developed to treat liver diseases. Despite the availability of increasing preclinical evidence of hawthorn, there is still ambiguity in confirming the pharmacological benefits and mechanisms of hawthorn extracts against liver-related pathological conditions. This review, therefore, includes significant advances in the pharmacological and molecular understanding of hawthorn extracts in liver disease management.
As demonstrated above, treatment with hawthorn extracts significantly reversed abnormalities related to hepatic injury, steatosis, inflammation, fibrosis, and cancer. These pathological conditions have been suggested to be closely and intricately linked with the risk of various liver diseases. Hence, hawthorn can be used as a therapeutic target for various hepatic diseases. In addition, the potential mechanisms covering antioxidant, apoptosis regulation, AMPK signaling, cholesterol metabolism, HSC inactivation, cell cycle arrest, and autophagy induction account for the pharmacological actions of hawthorn. Presumably, antioxidant defense by hawthorn extract against hepatic disorders is likely to be of interest, as many studies have determined the regulation of oxidative stress in hawthorn extract in reducing liver injury, fat accumulation, inflammation, and fibrosis. In terms of apoptosis, hawthorn extracts had a flexible impact in mediating apoptosis, in that hawthorn exerted hepatoprotective, anti-inflammatory, and antifibrotic activities through antiapoptosis in hepatic tissue, while the plant-induced apoptotic signal suppressed the cell viability of HepG2 cells. Moreover, the additional involvement of hawthorn in AMPK signaling, HSC inactivation, and hepatic cholesterol metabolism make the herb a possible agent for developing drugs for the management of liver diseases (Tables 1-4, Figures 1-4).
Collectively, liver diseases are a leading cause of worldwide morbidity and mortality. Recently, cases of HCC, ALD, NAFLD, and viral hepatitis have been increasing [102]. First, hawthorn possesses marked hepatoprotective, antisteatotic, anti-inflammatory, and antifibrotic effects against alcohol-induced liver injury, liver weight gain, fat deposition, hepatic inflammatory cell aggregation, and hepatic fibrosis. The beneficial properties of C. pinnatifida and C. oxyacantha against alcohol may be mainly implicated in ALDH and CYP2E1 enzyme-modulating activities and antioxidant effects, suggesting that these species can inhibit the overaccumulation of acetaldehyde, efficiently scavenge ROS attack, and reduce oxidation induced by alcohol.
Second, hawthorn treats NAFLD and metabolic syndromes, including diabetes, obesity, and hyperlipidemia. Supported by a large number of available preclinical results, hawthorn extract antagonized the significant changes in a variety of NAFLD rodent models. Specifically, hawthorn extracts were potent in reducing lipid content, inflammatory cell infiltration, and the expression of cytokines in liver tissue, thereby improving simple steatosis and steatohepatitis, mainly through antioxidant and AMPK signaling. The coordinated regulation of hawthorn extract on steatosis and inflammation may effectively prevent NASH-related fibrosis. Unfortunately, there was no preclinical evidence relating to the antifibrotic activity of hawthorn extracts in experimental models induced by Western diets, but the extract reduced liver fibrosis induced by CCl 4 and alcohol treatment. Hence, this field merits further research. Nevertheless, hawthorn extracts might be an effective regulator of metabolic changes that occur during NAFLD because an increasing amount of experimental data support that pharmacological effects of the herb are antidiabetic, antiobetic, and hypolipidemic, resulting in low risks of metabolic syndrome and cardiovascular diseases. Hence, it is conceivable that hawthorn extracts, specifically haw pectin and polyphenols from C. pinnatifida, act as potent anti-NAFLD drugs that orchestrate complex metabolic changes occurring in NAFLD, thereby treating hepatic steatosis and inflammation.
Third, hawthorn extracts may be involved in the treatment of HCC, which is the most common and aggressive form of liver cancer, with high morbidity and mortality.
Various curative therapies, including liver transplantation, surgical hepatectomy, and local ablation, are suitable for almost all early-stage cases. However, late diagnosis, inadequate hepatic reserves, and metastasis have lowered the therapeutic effects and 5-year survival rates of available treatment options [103]. Specifically, conventional chemotherapeutic agents often induce side effects by generating oxidative stress in non-targeted normal tissues. Similar to chemotherapy with cisplatin and 5-fluorouracil, hawthorn extracts also displayed anticancer effects against HepG2 cells. However, the abundance of antioxidant and hepatoprotective compounds constituting hawthorn extracts may reduce toxicity against normal cells. Although the effects of antioxidant and cytotoxic effects of hawthorn extract in HCC still need to be investigated, the triterpenoids, phenylpropanoids, and lignans obtained from C. pinnatifida might be crucial chemical groups for the control of HCC, as demonstrated above.
The present review also revealed the various species, parts, and compounds of hawthorn that were used to reduce hepatotoxicity, hepatic fat deposition, liver inflammation, fibrosis, and cancer in animal and cellular studies. The major species of hawthorn treated for alleviating hepatic pathological conditions are C. pinnatifida, C. oxyacantha, and C. monogyna. Among them, the fruits of C. pinnatifida can play a crucial role in improving hepatocytes overwhelmed by metabolic triggers leading to NAFLD by reducing oxidative stress and activating AMPK and NIK signaling. C. oxyacantha leaves and flowers may treat NASH-related fibrosis because the plant actively reduced hepatic fibrotic septa and collagen synthesis by CCl 4 via HSC inactivation and antioxidant processes. C. monogyna buds and fruits may have selective cytotoxicity against HCC, with no harmful effects on normal cells because of their abundant antioxidant substances. The specific groups of active ingredients of hawthorn have been shown to be responsible for the following beneficial actions: (1) polyphenols obtained from hawthorn extracts displayed hepatoprotective and anti-inflammatory actions by regulating apoptosis and oxidative stress. (2) Haw pectin isolated from hawthorn fruits enhanced the clearance of hepatic accumulation of lipids through AMPK-dependent regulation, reduced hepatic oxidative stress and hepatic cholesterol catabolism with the regulation of hepatic inflammation via NFκB inactivation.
(3) Triterpenoids, phenylpropanoids, and lignans of hawthorn plant were shown to have anticancer effects against HCC cell lines. In particular, vitexin, hyperoside, and corosolic acid were found in hawthorn to be among the major active ingredients primarily contributing to the bioactive activities of hawthorn against various liver diseases [104][105][106][107][108][109], and these compounds need further investigation to evaluate their efficacy.
In summary, the efficacy of hawthorn extract can be linked to ameliorating pathological conditions, including liver toxicity, steatosis, inflammation, fibrosis, and cancer of various hepatic disorders. The antioxidant mechanism of hawthorn extract may be crucial for the control of hepatic injury, steatosis, inflammation, and fibrosis. In addition to reducing oxidative stress in hepatic tissue by hawthorn extract, AMPK activation and antiapoptotic signaling also account for the improvement of hepatic steatosis and inflammation. Thus, given the role of hawthorn extracts in the regulation of hepatic disorders, the plant can contribute to the treatment of ALD, NAFLD, and HCC, as well as improve liver injury. However, further in vivo and clinical studies need to be elaborately designed and performed to confirm the clinical application of hawthorn extract and its compounds.

Conclusions
In conclusion, the present review demonstrates that hawthorn extracts have benefits against hepatic toxicity, fat deposition, inflammation, fibrosis, and cancer. The pharmacological activities of hawthorn extracts may be mainly due to reduced hepatic oxidative stress, which prevents excessive ROS attack and induces consequent hepatocellular function recovery. In addition, the regulation of AMPK, NIK, apoptosis, cholesterol metabolism, HSC activation, cell cycle arrest, and autophagy by hawthorn extracts is involved in its modulatory role in hepatic pathologic conditions. Therefore, hawthorn extracts may be promising and safe in treating hepatic disorders, even though in-depth and elaborate investigations on the efficacy, safety, and mechanism of action of the plant against liver diseases are needed.